SmPC change is the whole thing [Power / Sample Size]

posted by alejandro_jo1990 – Spain, 2022-09-01 18:18 (93 d 20:56 ago) – Posting: # 23255
Views: 925

»Dear Helmut, vielen dank for the fast answer (I truly miss my times as assistenzarzt in München)

I will try to give a broader scope. It's, at the and, a discussion between my colleagues from medical affairs versus clinical pharmacology/regulatory
A formulation is commercialized and appears to be absorbed faster than the free substance (its a lysinate as I recall). That is known from in vitro release, chemical data and some bad studies or maybe because their parents told them that (so SmPC gives the same clinical pharmacology properties in PK as the free substance).

Medical Affairs position: if wanted to include some marketing in the package to say that absorption is faster than other substance. So, if we design a trial and demosntrate superiority of therapeutic effect at 10 minutes we are good (not probably aware of the monstruous N, but ok).

R&D: A therapeutic trial only lets your marketing go in that direction. You cannot use a therapeutic action to support PK changes in the clinical pharmacology section of SmPC. You need a Phase I trial. If we want faster absorption in overall, use a T test to calculate an N for the differences in Cmax as expected or after a pilot (assuming it falls into the therapeutic range) or if you specifically wan it, you might need to demonstrate faster absorption at than point (ie. 10m). There the question: if we aimed to design it (technical stuff, I'm aware of the terrible N, especially as the clinical setting would call for a parallel design), would we need to adress superiority of the PK endpoint (logAUC10 or logConc a 10m???) uing t-test.

❝ Not sure, what you mean. If you want to avoid a clinical trial and bridge to the safety/efficacy data of the ‘old’ formulation

The point is (above) to demonstrate faster abosrption in overall or at acertain point. Your statement makes me raise some questions:
1. Being an IR, hence should not eiste the risk of dose dumping, do we also need to demonstrate BE for AUC (extent?) or only superiority of PK is ok?
2. If we fall into the therapeutic range (if it's wide we can assume that, what if its narrow?), can we still use Cmax and assume an increase for calculations? Or even if it's at at ceratin point, the Cmax will be increased accordingly, so all my doubts apply again.
4. So what if the therapeutic range is narrow?
5. If all is wrong, how do you design a trial to demonstrate faster absorption in overall or at a certain point? I've seen many FIH seeing that just because it's seen, but to design specifically for that??

PS Im truly aware of the whole thing being 0 clinically relevant, but I see it as an opportunity to learn.

Sorry for the long long post,

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